1. TDP-43 and PINK1 mediate CHCHD10S59L mutation–induced defects in Drosophila and in vitro.
- Author
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Baek, Minwoo, Choe, Yun-Jeong, Bannwarth, Sylvie, Kim, JiHye, Maitra, Swati, Dorn II, Gerald W., Taylor, J. Paul, Paquis-Flucklinger, Veronique, and Kim, Nam Chul
- Subjects
AMYOTROPHIC lateral sclerosis ,DROSOPHILA melanogaster ,HELA cells ,FRONTOTEMPORAL dementia ,DROSOPHILA ,DROSOPHILIDAE - Abstract
Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) can cause amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). However, the underlying mechanisms are unclear. Here, we generate CHCH10
S59L -mutant Drosophila melanogaster and HeLa cell lines to model CHCHD10-associated ALS-FTD. The CHCHD10S59L mutation results in cell toxicity in several tissues and mitochondrial defects. CHCHD10S59L independently affects the TDP-43 and PINK1 pathways. CHCHD10S59L expression increases TDP-43 insolubility and mitochondrial translocation. Blocking TDP-43 mitochondrial translocation with a peptide inhibitor reduced CHCHD10S59L -mediated toxicity. While genetic and pharmacological modulation of PINK1 expression and activity of its substrates rescues and mitigates the CHCHD10S59L -induced phenotypes and mitochondrial defects, respectively, in both Drosophila and HeLa cells. Our findings suggest that CHCHD10S59L -induced TDP-43 mitochondrial translocation and chronic activation of PINK1-mediated pathways result in dominant toxicity, providing a mechanistic insight into the CHCHD10 mutations associated with ALS-FTD. Mutations in CHCHD10 can cause amyotrophic lateral sclerosis and frontotemporal dementia. The authors generate mutant Drosophila and HeLa cells to study the underlying mechanisms of CHCHD10S59L -induced degeneration and show it is mediated by TDP-43 and PINK1 pathways. [ABSTRACT FROM AUTHOR]- Published
- 2021
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